Methods and compositions for treating polycystic ovary syndrome

ABSTRACT

Polycystic ovary syndrome (PCOS) is characterized by elevated levels of androgens, cysts in the ovaries, and irregular periods. Women with PCOS present with additional symptoms, including hirsutism, alopecia, acne, infertility, weight gain, fatigue, depression and mood changes. The present disclosure provides new compounds, salts, compositions and uses thereof in the treatment of PCOS due to elevated adrenal androgens. Further, the present disclosure provides methods for treating PCOS due to elevated adrenal androgens.

CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.18/107,979, filed Feb. 9, 2023; which is a continuation of PCTApplication No. PCT/US2021/045780, filed Aug. 12, 2021; which claims thebenefit of U.S. Provisional Patent Application No. 63/064,863, filedAug. 12, 2020; which are incorporated herein by reference in theirentirety.

BACKGROUND

Polycystic ovary syndrome (PCOS) is one of the most common endocrinedisorders affecting an estimated 12% of reproductive aged women. Womenwith PCOS may have polycystic ovarian morphologic features, ovulatorydysfunction in the form of infrequent or prolonged menstrual periods,and hyperandrogenism in the form of excess male hormone levels. Thiscomplex disorder has both environmental influences, such as obesity andinsulin resistance, and inappropriate endocrine signaling from thehypothalamus and pituitary glands as contributors. Hyperandrogenismpresents clinically as hirsutism and acne and biochemically withelevated serum androgen levels. Androgen and androgen precursors can beproduced and secreted by the ovaries and also by the adrenal cortices inabout the same amount in response to stimulation by pituitary derivedluteinizing hormone (LH) to the ovaries and adrenocorticotropic hormone(ACTH) to the adrenal gland, respectively. Emerging data indicate thatPCOS patients can be categorized according to whether the source ofexcessive androgen is primarily from the ovaries, namely, functionalovarian hyperandrogenism (FOH), or the adrenal glands, namely,functional adrenal hyperandrogenism (FAH), both (FOH and FAH), orneither and attributable to either insulin resistance/obesity or ofunknown origin. A majority or about two-thirds of cases havefunctionally typical PCOS (PCOS-T) that is due to typical FOH,characterized by hyperresponsiveness of 17-hydroxyprogesterone (17-OHP).About one fifth of cases have functionally atypical FOH (PCOS-A),lacking 17-OHP hyperresponsiveness. Within these two FOH populations,about one-third may have both FOH and FAH. About 8% of PCOS cases areattributed to either obesity and the remainder are unknown or idiopathicin nature. Only about 3-5% PCOS cases are due to isolated FAH withandrogen responsiveness to ACTH.

SUMMARY

Adrenal androgen excess in PCOS appears to occur independently ofovarian androgen excess, suggesting it may represent an intrinsic, andpossible primary source of abnormal synthesis of adrenal androgens.Adrenal androgen excess of PCOS may not result from deficiencies inspecific enzymatic steps, rather it may represent an altered pituitaryresponsivity to corticotropin releasing factor (CRF) andadrenocorticotropic hormone (ACTH).

In an aspect, the present disclosure provides methods for treatingpolycystic ovary syndrome with functional ovarian hyperandrogenism andfunctional adrenal hyperandrogenism (PCOS-FOH+FAH) in a subject in needthereof, comprising administering a CRF₁ antagonist or pharmaceuticallyacceptable salt thereof.

In another aspect, the present disclosure provides methods for treatingpolycystic ovary syndrome with functional adrenal hyperandrogenism(PCOS-FAH) in a subject in need thereof, comprising administering a CRF₁antagonist or pharmaceutically acceptable salt thereof

In another aspect, the present disclosure provides methods for treatingpolycystic ovary syndrome (PCOS) in a subject in need thereof,comprising administering a CRF₁ antagonist or pharmaceuticallyacceptable salt thereof

In another aspect, the present disclosure provides methods for treatingpolycystic ovary syndrome (PCOS) in a subject in need thereof,comprising accessing a source of excessive androgen; and administering aCRF₁ antagonist or pharmaceutically acceptable salt thereof In someembodiments, the cosyntropin is administered at a dose about 1 μg/m². Insome embodiments, the cosyntropin is administered at a dose about 10μg/m². In some embodiments, the cosyntropin is administered at a doseabout 250 μg/m². In some embodiments, the source of excessive androgenis adrenal glands. In some embodiments, the source of excessive androgenis ovaries.

In some embodiments, the CRF₁ antagonist is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently ethyl or n-propyl; R³ is hydrogen, F, Cl, Br, methyl,trifluoromethyl, or methoxy; R⁴ is hydrogen, Br, —NR^(a)R^(b),methoxymethyl, n-butyl, acetamido, pyridin-4-yl, morpholin-4-yl,

R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl, —CH₂CH₂NH₂,—CH₂CH₂NHC(O)OC(CH₃)₃, or —CH₂CH₂NHCH₂CH₂CH₃.

In some embodiments, R³ is F, Cl, Br, methyl, or trifluoromethyl.

In some embodiments, R³ is Cl or Br.

In some embodiments, R⁴ is —NR^(a)R^(b), pyridin-4-yl, morpholin-4-yl,or

In some embodiments, R⁴ is morpholin-4-yl or

In some embodiments, R⁴ is —NR^(a)R^(b), and R^(a) and R^(b) areindependently C₁-C₃alkyl.

In some embodiments, the CRF₁ antagonist or a pharmaceuticallyacceptable salt thereof is3[4-bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-2, 5-dimethyl-7-(1 -propyl-butyl)-pyrazolo[1,5-α]pyrimidine.

In some embodiments, the CRF₁ antagonist or a pharmaceuticallyacceptable salt thereof is3-(4-bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dim ethyl-pyrazolo[1,5-α]pyrimidine.

In some embodiments, the CRF₁ antagonist or a pharmaceuticallyacceptable salt thereof is3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-α]pyrimidine.

In some embodiments, the CRF₁ antagonist is

or a pharmaceutically acceptable salt thereof

In some embodiments, the CRF₁ antagonist is

or a pharmaceutically acceptable salt thereof

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof

In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt thereof is selected from the group consisting of: Antalarminhydrochloride, CP-154,526, CP-376395 hydrochloride, NBI 27914hydrochloride, NBI 35965 hydrochloride, NGD 98-2 hydrochloride,Pexacerfont, R 121919 hydrochloride, SSR125543 (crinecerfont), andSN003.

In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt is administered in a dose of about 5 mg to about 400 mg total dailydose to the subject. In some embodiments, the CRF₁ antagonist orpharmaceutically acceptable salt is administered in a dose of about 300mg total daily dose to the subject. In some embodiments, the CRF₁antagonist or pharmaceutically acceptable salt is administered in a doseof about 200 mg total daily dose to the subject. In some embodiments,the CRF₁ antagonist or pharmaceutically acceptable salt is administeredin a dose of about 150 mg total daily dose to the subject. In someembodiments, the CRF₁ antagonist or pharmaceutically acceptable salt isadministered in a dose of about 100 mg total daily dose to the subject.In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt is administered in a dose of about 75 mg total daily dose to thesubject. In some embodiments, the CRF₁ antagonist or pharmaceuticallyacceptable salt is administered in a dose of about 50 mg total dailydose to the subject. In some embodiments, the CRF₁ antagonist orpharmaceutically acceptable salt is administered in a dose of about 25mg total daily dose to the subject. In some embodiments, the CRF₁antagonist or pharmaceutically acceptable salt is administered in a doseof about 10 mg total daily dose to the subject. In some embodiments, theCRF₁ antagonist or pharmaceutically acceptable salt thereof isadministered as a pharmaceutical composition.

In some embodiments, an adrenocorticotropic hormone (ACTH) level isreduced by at least 5% from baseline. In some embodiments, anadrenocorticotropic hormone (ACTH) level is reduced by at least 10% frombaseline. In some embodiments, a dehydroepiandrosterone (DHEAS) level isreduced by at least 5% from baseline. In some embodiments, adehydroepiandrosterone sulfate (DHEAS) level is reduced by at least 10%from baseline. In some embodiments, the androstenedione (A4) level isreduced by at least 5% from baseline. In some embodiments, theandrostenedione (A4) level is reduced by at least 10% from baseline. Insome embodiments, the 1β-hydroxyandrostenedione (11OHA4) level isreduced by at least 5% from baseline. In some embodiments, the1β-hydroxyandrostenedione (11OHA4) level is reduced by at least 10% frombaseline. In some embodiments, the 11β-hydroxytestosterone (11OHT) levelis reduced by at least 5% from baseline. In some embodiments, the11β-hydroxytestosterone (11OHT) level is reduced by at least 10% frombaseline.

In some embodiments, a reduced ACTH, DHEAS, A4, 11OHA4 or 11OHT levelfrom baseline is maintained for at least 24 hours. In some embodiments,a reduced ACTH, DHEAS, A4, 11OHA4 or 11OHT level from baseline ismaintained for at least 4 weeks.

In another aspect, the present disclosure provides methods for treatingpolycystic ovary syndrome with functional adrenal hyperandrogenism(PCOS-FAH) in a subject in need thereof, comprising administering apharmaceutical composition comprising Compound 3:

or a pharmaceutically acceptable salt or solvate thereof

In another aspect, the present disclosure provides methods for treatingpolycystic ovary syndrome with functional ovarian hyperandrogenism andfunctional adrenal hyperandrogenism (PCOS-FOH+FAH) in a subject in needthereof, comprising administering a pharmaceutical compositioncomprising Compound 3:

or a pharmaceutically acceptable salt or solvate thereof

In some embodiments, the Compound 3 is administered at a dose betweenabout 1 mg/day and about 400 mg/day.

In some embodiments, the pharmaceutical composition comprises about 25mg of Compound 3, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 50 mg of Compound 3, or a pharmaceutically acceptable salt orsolvate thereof In some embodiments, the pharmaceutical compositioncomprises between about 75 mg of Compound 3, or a pharmaceuticallyacceptable salt or solvate thereof In some embodiments, thepharmaceutical composition comprises about 100 mg of Compound 3, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises about 200 mg ofCompound 3, or a pharmaceutically acceptable salt or solvate thereof Insome embodiments, the pharmaceutical composition comprises between about1 mg and about 300 mg of Compound 3, or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments, the pharmaceutical composition is in the form ofmicroparticles. In some embodiments, the average size of themicroparticles is between about 1 μm to about 20 μm. In someembodiments, the average size of the microparticles is between about 5μm to about 15 μm. In some embodiments, the average size of themicroparticles is less than about 10

In some embodiments, the pharmaceutical composition is in the form of acapsule or a tablet. In some embodiments, the capsule is a hard gelatincapsule. In some embodiments, the capsule is a soft gelatin capsule.

In some embodiments, the capsule is formed using materials selected fromthe group consisting of natural gelatin, synthetic gelatin, pectin,casein, collagen, protein, modified starch, polyvinylpyrrolidone,acrylic polymers, cellulose derivatives, and any combinations thereof Insome embodiments, the pharmaceutical composition is free of additionalexcipients. In some embodiments, the pharmaceutical composition furthercomprises one or more pharmaceutically acceptable excipients. In someembodiments, the pharmaceutical composition is in the form of a tablet.In some embodiments, the pharmaceutical composition further comprisesone or more pharmaceutically acceptable excipients.

In some embodiments, the subject is a pediatric patient. In someembodiments, the subject is from about 9 years old to about 18 yearsold. In some embodiments, the subject is from about 8 years of age toabout 55 years of age. In some embodiments, the subject is an adultpatient.

In some embodiments, the subject is treated for a period of about 2weeks to about 36 weeks. In some embodiments, the subject is treated fora period of about 1 month to 12 months. In some embodiments, the subjectis treated for a period of about 10 months to 50 years.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different embodiments, andits several details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent publications and patents or patent applicationsincorporated by reference contradict the disclosure contained in thespecification, the specification is intended to supersede and/or takeprecedence over any such contradictory material.

DETAILED DESCRIPTION

While various embodiments of the invention have been shown and describedherein, it will be obvious to those skilled in the art that suchembodiments are provided by way of example only. Numerous variations,changes, and substitutions may occur to those skilled in the art withoutdeparting from the invention. It should be understood that variousalternatives to the embodiments of the invention described herein may beemployed.

Polycystic Ovary Syndrome (PCOS)

Polycystic ovarian syndrome (PCOS) is a heterogeneous disorder withmultiple phenotypes and is one of the most common endocrine metabolicdisorders in reproductive aged women. PCOS was first diagnosed anddescribed as a syndrome of oligo-amenorrhea and polycystic ovaries thatwas variably accompanied by hirsutism, acne, and obesity. There arevarious diagnostic criteria for adolescent and adult patientsconsidering the core diagnostic features, such as hyperandrogenism,persistent ovulatory dysfunction, and polycystic ovarian morphology(PCOM). The exact etiology of this disorder is not entirely clear,however, both genetic and environmental factors seem to play roles incausing the disorder. Generally, PCOS presents as a phenotype reflectinga self-perpetuating vicious cycle involving neuroendocrine, metabolic,and ovarian dysfunction and is characterized by excessive ovarian and/oradrenal androgen secretion. For example, intrinsic ovarian factors suchas altered steroidogenesis and factors external to the ovary such ashyperinsulinemia contribute to the excessive ovarian androgenproduction. The classic ovarian phenotype of enlarged ovaries withstring-of-pearl morphology and theca interstitial hyperplasia reflectsandrogen exposure; this morphology has also been observed in women withcongenital adrenal hyperplasia (CAH).

In order to attempt to understand the pathophysiology of PCOS, it isimportant to understand the molecular basis of steroidogenesis andandrogen source, production and physiology. Under normal circumstancesin women, the ovaries and adrenal glands contribute about equally totestosterone production. Approximately half of testosterone originatesfrom direct testosterone secretion by the ovaries and adrenal glands,whereas half is produced by peripheral conversion of circulatingandrostenedione, which itself arises from approximately equal ovarianand adrenal secretion. Androgen production is not under direct negativefeedback regulation by the neuroendocrine system in females, as is thecase for estradiol and cortisol secretion. Androgens are secreted byboth the ovaries and adrenal glands in response to their respectivetropic hormones, LH and ACTH. The zona reticularis of the adrenal glandresembles the theca cell compartment of the ovary in its expression ofthe core enzymatic pattern for androgen production.

PCOS patients can be functionally categorized as distinct subtypes basedon the source of androgen excess listed in Table 1 below. Androgenexcess can be derived from the ovaries, the adrenal glands, both, orneither. Primary PCOS is the most common variety of PCOS without anyknown cause and a proposed theory suggests that functional ovarianhyperandrogenism (FOH) along with disturbance ofhypothalamo-pituitary-ovarian (HPO) axis function may be the underlyingcause. Further, functional adrenal hyperandrogenism (FAH) other than HPOaxis disturbance may be explained for a certain population of PCOSpatients. The PCOS patients with primary FAH may experience an average50% increase in adrenal volume that correlates with hyperandrogenemiaseverity.

TABLE 1 Functional classification of PCOS based on source of androgenexcess PCOS DAST Functional GnRHag Test Testosterone ACTH testPrevalence Type Source of Androgen 17OHP Response Response DHEA ResponseAmong PCOS PCOS-T Primary FOH (typical FOH) High

High in 92.5% High in 28% (associated FAH) 67%

PCOS-A Primary FOH (atypical FOH) Normal

High High in 30% (associated FAH) 20%  Primary FAH (isolated FAH) NormalNormal High 5% PCOS without FOH or FAH Normal Normal Normal 8% (PCOS-Aof obesity or idiopathic PCOS-A)

indicates data missing or illegible when filed

Test procedures to determine the source of androgen are listed below inTable 2. The ovarian hyperandrogenism of PCOS is demonstrated directlyby the GnRHag test or the hCG test and in combination with thedexamethasone androgen-suppression test (DAST). The GnRHag testdetermines the coordinated function of the ovarian follicle. Leuprolideacetate 10 μg/kg sc (or a comparable dose of any other short-actingGnRHag) stimulates endogenous LH and FSH release that peaks at 3-4 hoursand persists for 24 hours; this in turn stimulates increased secretionof sex steroids and their precursors, with serum levels peaking at 18-24hours. In the absence of evidence of a steroidogenic block, an elevated17OHP response is typical of PCOS. Ovarian steroidogenic enzymedeficiency, which is rare, can be detected by an abnormal pattern ofsteroid intermediates in response to the test. hCG is an LH analog: 5000IU intramuscularly stimulates steroidogenic responses comparable withthose of a GnRHag test at 24 hours. DAST indirectly tests for ovariansource of androgens by suppressing ACTH-dependent androgen production ofandrogens. In the presence of normal adrenocortical suppression aninappropriately elevated serum testosterone post-DAST indicates anACTH-independent source of androgen, which is ordinarily of ovarianorigin.

Adrenal hyperandrogenism may be demonstrated by a rapid ACTH test:cosyntropin is administered iv and peak steroid responses occur at 15-60minutes. An elevated DHEA post this test indicates an ACTH-dependentsource of androgen, which is ordinarily of adrenal origin. The test maybe performed using cosyntropin 250 μg, this is a supramaximal dose.Lower doses of cosyntropin may be used (10 μg/m²) which elicit a similarpeak response. A low-dose ACTH test (1.0-μg cosyntropin) may be used andmay be more physiologic. It usually elicits nearly as great a peakresponse that promptly wanes, and in PCOS, does not elicit such a widespectrum of elevated steroid intermediates as do larger doses.

TABLE 2 Methods to determine source of female androgen excess TestRationale Method Outcome Measures Interpretation

GnRHag Endogenous LH and FSH release Leuprolide acetate 10 μg/kg scOvarian steroid secretion 17OHP >152 ng/dL stimulates coordinatedfunction (for maximum stimulation) peaks at 20-24 h withoutsteroidogenic of ovarian follicles block indicates typical FOH (PCOS-T)hCG Exogenous administration of LH hCG 3000 IU/m² Ovarian steroidsecretion 17OHP >152 ng/dL analog stimulates theca-interstitial (formaximum stimulation) peaks at 24 h without steroidogenic cells blockindicates typical FOH (PCOS-T) LDAST Long DAST: dexamethasoneDexamethasone 0.5 mg QID Free testosterone, DHEAS, Free testosterone ≥8pg/mL profoundly suppresses adrenal per os × 4-5 d cortisol: sampleearly with DHEAS <70 and androgens over several days morning d 5cortisol <1 μg/dL characteristic of FOH SDAST Short DAST: dexamethasonerapidly Dexamethasone 0.25 mg/m² Total testosterone, cortisol: Totaltestosterone >25 ng/mL suppresses adrenal testosterone per os at 12 noonsample 4

 (4 h) cortisol <5 μg/dL and cortisol suggests FOH ACTH Exogenous ACTHstimulates adrenal Cosyntropin ≥10 μg/m² DHEA, 17OHP: steroid DHEA1500-3000 μg/dL steroidogenesis (for maximum stimulation) intermediates,cortisol without steroidogenic peak at 30-60 min block indicates FAH

indicates data missing or illegible when filed

Corticotropin Releasing Factor

Currently, no single universal treatment for PCOS is available. As aresult, current treatments tend to be individualized and adapted to theactual needs of the individual patient. Furthermore, treatment may besymptom-oriented. For example, targets for pharmacological treatment mayinclude androgen excess. For PCOS patients with elevated adrenalandrogens, FOH+FAH and PCOS-FAH patients, in some embodiments,pharmacological treatment, such as corticotropin releasing factor (CRF)receptor antagonist targeting ACTH production may be used.

Corticotropin releasing factor (CRF) is a 41 amino acid peptide that isthe primary physiological regulator of proopiomelanocortin (POMC)derived peptide secretion from the anterior pituitary gland. In additionto its endocrine role at the pituitary gland, immunohistochemicallocalization of CRF has demonstrated that the hormone has a broadextrahypothalamic distribution in the central nervous system andproduces a wide spectrum of autonomic, electrophysiological andbehavioral effects consistent with a neurotransmitter or neuromodulatorrole in the brain. There is also evidence that CRF plays a significantrole in integrating the response in the immune system to physiological,psychological, and immunological stressors.

CRF has been implicated in psychiatric disorders and neurologicaldiseases including depression and anxiety, as well as the following:Alzheimer's disease, Huntington's disease, progressive supranuclearpalsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy,migraine, alcohol and substance abuse and associated withdrawalsymptoms, obesity, metabolic syndrome, congenital adrenal hyperplasia(CAH), Cushing's disease, hypertension, stroke, irritable bowelsyndrome, stress-induced gastric ulceration, premenstrual syndrome,sexual dysfunction, premature labor, inflammatory disorders, allergies,multiple sclerosis, visceral pain, sleep disorders, pituitary tumors orectopic pituitary derived tumors, chronic fatigue syndrome, andfibromyalgia.

CRF is believed to be the major physiological regulator of the basal andstress-induced release of adrenocorticotropic hormone (“ACTH”),β-endorphin, and other proopiomelanocortin (“POMC”)-derived peptidesfrom the anterior pituitary. Secretion of CRF causes release of ACTHfrom corticotrophs in the anterior pituitary via binding to the CRF₁receptor, a member of the class B family of G-protein coupled receptors.

Due to the physiological significance of CRF₁, the development ofbiologically-active small molecules having significant CRF receptorbinding activity and which are capable of antagonizing the CRF₁ receptorremains a desirable goal and has been the subject of ongoing researchand development for the treatment of anxiety, depression, irritablebowel syndrome, post-traumatic stress disorder, and substance abuse, andcongenital adrenal hyperplasia.

The pituitary hormone ACTH, under the control of hypothalamiccorticotropin-releasing factor (CRF), stimulates uptake of cholesteroland drives the synthesis of pregnenolone initiating steroidogenesis inthe adrenal gland. The adrenal cortex is comprised of three zones, whichproduce distinct classes of hormones many of which are driven by ACTHmobilizing cholesterol through this pathway. The middle layer, the zonareticularis is responsible for the production of androgens such as DHEA,DHEAS and androstenedione, (A4) the precursor to testosterone (T) anddihydrotestosterone (DHT). This layer is also responsible for theproduction of the 11-oxyandrogens, 11β-hydroxyandrostenedione (11OHA4)and 11β-hydroxytestosterone (110HT), which are major bioactiveandrogens, particularly in women. Due to an unknown cause in PCOSpatients with elevated androgens, the zone reticularis displays ahyperresponsiveness to ACTH resulting excessive levels of DHEA, DHEAS,11OHA4, 11OHT and A4. The excessive ACTH stimulation causes hypertrophyof the zona reticularis resulting in adrenal hyperplasia and clinicallymanifests with physical features typical of PCOS and hyperandrogenism.Reducing the stimulatory effect on the pituitary's ACTH secretion byinhibiting the CRF₁ receptor is expected is reduce excessive androgensynthesis from the ACTH responsive zone of the adrenal gland in PCOS.The normalization of elevated androgen levels in the short term would beexpected to ameliorate cardinal features of PCOS—hirsutism, acne andmenstrual irregularities—over the long term.

Certain Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes 10% level oferror for the device or method being employed to determine the value.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and to “and/or.”

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, and preferably having from one to five carbon atoms (i.e.C₁-C₅alkyl). In some embodiments, an alkyl comprises one to four carbonatoms (i.e., C₁-C₄alkyl).). In some embodiments, an alkyl comprises oneto three carbon atoms (i.e., C₁-C₃alkyl).). In some embodiments, analkyl comprises one to two carbon atoms (i.e., C₁-C₂alkyl). In someembodiments, an alkyl comprises one carbon atom (i.e., C₁alkyl). Incertain embodiments, the alkyl group is selected from methyl, ethyl,1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl(tert-butyl), or 1-pentyl (n-pentyl). The alkyl is attached to the restof the molecule by a single bond. Unless stated otherwise specificallyin the specification, an alkyl group is optionally substituted by one ormore substituents such as those described herein.

The terms “comprise,” “have” and “include” are open-ended linking verbs.Any forms or tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. “Administering” a pharmaceutical composition may beaccomplished by injection, topical administration, and oraladministration or by other methods alone or in combination with otherknown techniques.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of thecomposition and not deleterious to the recipient thereof.

The term “pharmaceutical composition” means a composition comprising atleast one active ingredient, such as a steroid or a pharmaceuticallyacceptable salt thereof or a CRF₁ antagonist or a pharmaceuticallyacceptable salt thereof, whereby the composition is amenable toinvestigation for a specified, efficacious outcome in a mammal (forexample, without limitation, a human). Those of ordinary skill in theart will understand and appreciate the techniques appropriate fordetermining whether an active ingredient has a desired efficaciousoutcome based upon the needs of the artisan.

The term “supraphysiologic amount” describes glucocorticoid dose levelsthat are above the daily glucocorticoid requirement (production rate)found in healthy individuals.

The term “physiologic amount” describes glucocorticoid dose levels thatmeet the daily glucocorticoid requirement (production rate) found inhealthy individuals.

The term “hydrocortisone equivalents” as used herein is understood by aperson skilled in the art to be the conversion calculations needed to beconsidered when substituting one glucocorticoid for another as thepotency and duration of action of various glucocorticoids may vary.Hence, the term “hydrocortisone equivalents” is the standard used forcomparison of glucocorticoid potency.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

Compounds

Disclosed herein are CRF₁ antagonists or pharmaceutically acceptablesalt thereof such as Antalarmin hydrochloride, CP-154,526, CP-376395hydrochloride, NBI 27914 hydrochloride, NBI 35965 hydrochloride, NGD98-2 hydrochloride, Pexacerfont, R 121919 hydrochloride, SNO03, andSSR125543 (crinecerfont).

In one aspect, the CRF₁ antagonist or pharmaceutically acceptable saltthereof is selected from the group consisting of:n-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (Antalarmin hydrochloride),n-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehydrochloride (Pfizer CP154526),N-(1-Ethylpropyl)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-4-pyridinamine hydrochloride (Pfizer CP376395 hydrochloride),5-Chloro-N-(cyclopropylmethyl)-2-methyl-n-propyl-N′-(2,4,6-trichlorophenyl)-4,6-pyrimidinediaminehydrochloride (NBI27914 hydrochloride),(7S)-6-(Cyclopropylmethyl)-2-(2,4-dichlorophenyl)-7-ethyl-7,8-dihydro-4-methyl-6H-1,3,6,8a-tetraazaacenaphthylenehydrochloride (NBI35965 hydrochloride),N-(1-Ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methyl-2-pyrazinaminehydrochloride (NGD 98-2 hydrochloride),8-(6-Methoxy-2-methyl-3-pyridinyl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo[1,5-a]-1,3,5-triazin-4-amine(Pexacerfont),3-[6-(Dimethylamino)-4-methyl-3-pyridinyl]-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin-7-aminehydrochloride (R 121919 hydrochloride), andN-(4-Methoxy-2-methylphenyl)-1-[1-(methoxymethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-4-amine(SN003),(S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-l-yl)thiazol-2-amine (SSR125543).

Disclosed herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areindependently ethyl or n-propyl; R³ is H, Cl, Br, methyl,trifluoromethyl, or methoxy; R⁴ is H, Br, —NR^(a)R^(b), methoxymethyl,n-butyl, acetamido, pyridin-4-yl, morpholin-4-yl,

and R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl, —CH₂CH₂NH₂,—CH₂CH₂NHC(O)OC(CH₃)₃, or —CH₂CH₂NHCH₂CH₂CH₃.

In some embodiments, R¹ and R² are independently ethyl or n-propyl. Insome embodiments, R¹ is ethyl and R² is n-propyl. In some embodiments,R¹ is n-propyl and R² is ethyl. In some embodiments, R¹ and R² are bothethyl. In some embodiments, R¹ and R² are both n-propyl.

In some embodiments, R³ is hydrogen, Cl, Br, methyl, or trifluoromethyl.In some embodiments, R³ is hydrogen, Cl, Br, or methyl. In someembodiments, R³ is hydrogen, Cl, or Br. In some embodiments, R³ ishydrogen. In some embodiments, R³ is Cl. In some embodiments, R³ is Br.

In some embodiments, R⁴ is hydrogen, Br, —NR^(a)R^(b), methoxymethyl,n-butyl, acetamido, pyridin-4-yl, morpholin-4-yl

In some embodiments, R⁴ is Br, —NR^(a)R^(b), methoxymethyl, n-butyl,acetamido, pyridin-4-yl, morpholin-4-yl

In some embodiments, R⁴ is —NR^(a)R^(b), methoxymethyl, n-butyl,acetamido, pyridin-4-yl, morpholin-4-yl, or

In some embodiments, R⁴ is —NR^(a)R^(b), n-butyl, acetamido,pyridin-4-yl, morpholin-4-yl, or

In some embodiments, R⁴ is —NR^(a)R^(b),pyridin-4-yl, morpholin-4-yl, or

In some embodiments, R⁴ is morpholin-4-yl or

In some embodiments, R⁴ is morpholin-4-yl. In some embodiments, R⁴ is

In some embodiments, R⁴ is NR^(a)R^(b) and R^(a) and R^(b) areindependently C₁-C₃alkyl.

Disclosed herein is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ is H, Cl, Br,methyl, trifluoromethyl, or methoxy; R⁴ is H, Br, —NR^(a)R^(b),methoxymethyl, n-butyl, acetamido, pyridin-4-yl, morpholin-4-yl,

and R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl, —CH₂CH₂NH₂,—CH₂CH₂NHC(O)OC(CH₃)₃, or —CH₂CH₂NHCH₂CH₂CH₃—CH₂CH₂NHCH₂CH₂CH₃.

Disclosed herein is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² aren-propyl; R³ is H, Cl, Br, methyl, trifluoromethyl, or methoxy; R⁴ is H,Br, —NR^(a)R^(b), methoxymethyl, n-butyl, acetamido, pyridin-4-yl,morpholin-4-yl,

and R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl, —CH₂CH₂NH₂,—CH₂CH₂NHC(O)OC(CH₃)₃, or —CH₂CH₂NHCH₂CH₂CH₃.

Disclosed herein is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein R³ is Cl, Br,methyl, trifluoromethyl, or methoxy; R⁴ is H, Br, —NR^(a)R^(b),methoxymethyl, n-butyl, acetamido, pyridin-4-yl, morpholin-4-yl,

and R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl, —CH₂CH₂NH₂,—CH₂CH₂NHC(O)OC(CH₃)₃, or —CH₂CH₂NHCH₂CH₂CH₃.

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R³ may be hydrogen, Cl, Br, methyl, trifluoromethyl, ormethoxy. For a compound or pharmaceutically acceptable salt of Formula(I), (II), (III), and (IV), R³ may be Cl, Br, methyl, trifluoromethyl,or methoxy. For a compound or pharmaceutically acceptable salt ofFormula (I), (II), (III), and (IV), R³ may be Cl, Br, methyl, ortrifluoromethyl. For a compound or pharmaceutically acceptable salt ofFormula (I), (II), (III), and (IV), R³may be Cl, Br, or methyl. For acompound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R³ may be Cl. For a compound or pharmaceuticallyacceptable salt of Formula (I), (II), (III), and (IV), R³ may be Br. Fora compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R³ may be methyl.

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is Br, —NR^(a)R^(b), methoxymethyl, n-butyl,acetamido, pyridin-4-yl, morpholin-4-yl,

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is Br, methoxymethyl, n-butyl, acetamido,pyridin-4-yl, morpholin-4-yl,

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is Br, n-butyl, acetamido, pyridin-4-yl,morpholin-4-yl,

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is Br, acetamido, pyridin-4-yl, morpholin-4-yl,

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is Br, pyridin-4-yl, morpholin-4-yl,

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is pyridin-4-yl, morpholin-4-yl,

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is morpholin-4-yl,

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is

For a compound or pharmaceutically acceptable salt of Formula (I), (II),(III), and (IV), R⁴ is morpholin-4-yl.

Disclosed herein is3-[4-bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-2,5-dimethyl-7-(1-propyl-butyl)-pyrazolo[1,5-a]pyrimidine(Compound 1) or a pharmaceutically acceptable salt thereof:

Disclosed herein is3-(4-bromo-2-(2-methyl-2H[1,2,4]triazol-3-yl)-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine(Compound 2) or a pharmaceutically acceptable salt thereof:

Disclosed herein is3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine(or alternatively 4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine)(Compound 3) or a pharmaceutically acceptable salt thereof:

In some embodiments,4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholineis referred to as Compound 3. In some embodiments,3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidineis referred to as Compound 3.

In one aspect, the CRF₁ antagonist or pharmaceutically acceptable saltthereof may be an astressin. An astressin generally refers to anonselective corticotropin releasing hormone antagonist that reduces thesynthesis of ACTH and cortisol.

Pharmaceutical Compositions

Disclosed herein are pharmaceutical compositions comprising a compoundor pharmaceutically acceptable salt described herein. In certainembodiments, the composition comprises a steroid or a pharmaceuticallyacceptable salt thereof and a CRF₁ antagonist or pharmaceuticallyacceptable salt thereof as disclosed above. In some embodiments, thesteroid or a pharmaceutically acceptable salt thereof is exogenousglucocorticoids (GC) or a pharmaceutically acceptable salt thereof.

Dosage Form

In some embodiments, the pharmaceutical compositions described hereinare provided in unit dosage form. As used herein, a “unit dosage form”is a composition containing an amount of a compound or pharmaceuticallyacceptable salt described herein that is suitable for administration toan animal, preferably mammal, subject in a single dose, according togood medical practice. The preparation of a single or unit dosage formhowever, does not imply that the dosage form is administered once perday or once per course of therapy. Such dosage forms are contemplated tobe administered once, twice, thrice or more per day and may beadministered as infusion over a period of time (e.g., from about 30minutes to about 2-6 hours), or administered as a continuous infusion,and may be given more than once during a course of therapy, though asingle administration is not specifically excluded.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

In some embodiments, the pharmaceutical compositions described hereinare formulated as oral dosage forms. Suitable oral dosage forms include,for example, tablets, pills, sachets, or capsules. In some embodiments,the pharmaceutical composition comprises one or more additionalpharmaceutically acceptable excipients. See, e.g., Remington: TheScience and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co.,Easton, PA (2005) for a list of pharmaceutically acceptable excipients.

Capsule

In some embodiments, the pharmaceutical composition is formulated as acapsule. In some embodiments, the pharmaceutical composition isformulated as a hard gel capsule. In some embodiments, thepharmaceutical composition is formulated as a soft gel capsule.

In some embodiments, the capsule is formed using materials whichinclude, but are not limited to, natural or synthetic gelatin, pectin,casein, collagen, protein, modified starch, polyvinylpyrrolidone,acrylic polymers, cellulose derivatives, or any combinations thereof Insome embodiments, the capsule is formed using preservatives, coloringand opacifying agents, flavorings and sweeteners, sugars,gastroresistant substances, or any combinations thereof. In someembodiments, the capsule is coated. In some embodiments, the coatingcovering the capsule includes, but is not limited to, immediate releasecoatings, protective coatings, enteric or delayed release coatings,sustained release coatings, barrier coatings, seal coatings, orcombinations thereof. In some embodiments, a capsule herein is hard orsoft. In some embodiments, the capsule is seamless. In some embodiments,the capsule is broken such that the particulates are sprinkled on softfoods and swallowed without chewing. In some embodiments, the shape andsize of the capsule also vary. Examples of capsule shapes include, butare not limited to, round, oval, tubular, oblong, twist off, or anon-standard shape. The size of the capsule may vary according to thevolume of the particulates. In some embodiments, the size of the capsuleis adjusted based on the volume of the particulates and powders. Hard orsoft gelatin capsules may be manufactured in accordance withconventional methods as a single body unit comprising the standardcapsule shape. A single-body soft gelatin capsule typically may beprovided, for example, in sizes from 3 to 22 minims (1 minims beingequal to 0.0616 ml) and in shapes of oval, oblong or others. The gelatincapsule may also be manufactured in accordance with conventionalmethods, for example, as a two-piece hard gelatin capsule, sealed orunsealed, typically in standard shape and various standard sizes,conventionally designated as (000), (00), (0), (1), (2), (3), (4), and(5). The largest number corresponds to the smallest size. In someembodiments, the pharmaceutical composition described herein (e.g.,capsule) is swallowed as a whole.

In some embodiments, the capsule comprises one or more pharmaceuticallyacceptable excipients. In some embodiments, the capsule is free ofadditional excipients.

In some embodiments, a capsule is developed, manufactured andcommercialized for a drug substance that is insoluble. In someembodiments, a drug substance is insoluble if solubility is less than0.002 mg/mL in water. In some embodiments, the capsule has a dosestrength of up to 200 mg. In some embodiments, drug substance in thecapsule is immediately released in a dissolution medium using USPapparatus I. In some embodiments, drug substance in the capsule isimmediately released in a dissolution medium using USP apparatus II.

Tablet

Poorly soluble drugs may be difficult to formulate using standardtechnologies such as high shear wet granulation. Optimum delivery ofpoorly soluble drugs may require complex technologies such as solidsolutions amorphous dispersions (hot melt extrusion or spray drying),nano-formulations or lipid-based formulations. Hydrophobic drugsubstances may be considered poorly soluble according to USP criteriaand may be known to be difficult to granulate with water and otherexcipients. This is likely due to most known excipients for immediaterelease formulations being water soluble or water-swellable. Making atablet of a high dose drug substance that is poorly soluble may requirea high concentration of the drug substance. However, as the drugconcentration is increased above a certain level, formation of granulesmay become more and more difficult. Furthermore, at a certain drug load,it may become impossible.

In some embodiments, the pharmaceutical composition is formulated as atablet.

In some embodiments, the tablet is made by compression, molding, orextrusion, optionally with one or more pharmaceutically acceptableexcipient. In some embodiments, compressed tablets are prepared bycompressing a compound or pharmaceutically acceptable salt describedherein in a free-flowing form, optionally mixed with pharmaceuticallyacceptable excipients. In some embodiments, molded tablets are made bymolding a mixture of the powdered a compound or pharmaceuticallyacceptable salt described herein, moistened with an inert liquiddiluent. In some embodiments, the tablet is prepared by hot-meltextrusion. In some embodiments, extruded tablets are made by forcing amixture comprising a compound or pharmaceutically acceptable saltdescribed herein, through an orifice or die under controlled conditions.In some embodiments, the tablet is coated or scored. In someembodiments, the tablet is formulated so as to provide slow orcontrolled release of a compound or pharmaceutically acceptable saltdescribed herein. In some embodiments, a tablet is developed,manufactured and commercialized for a drug substance that is insoluble.In some embodiments, a drug substance is insoluble if solubility is lessthan 0.002 mg/mL in water. In some embodiments, the tablet has a dosestrength of up to 200 mg. In some embodiments, drug substance in thetablet is immediately released in a dissolution medium using USPapparatus I. In some embodiments, drug substance in the tablet isimmediately released in a dissolution medium using USP apparatus II.

In some embodiments, the tablet size is less than about 1000 mg, lessthan about 800 mg, less than about 600 mg, less than about 400 mg, lessthan about 200 mg, less than about 100 mg or less than 50 mg. In someembodiments, the tablet has a dose strength of more than about 10 mg,more than about 50 mg, more than about 100 mg, more than about 150 mg,more than about 200 mg, or more than about 250 mg. In some embodiments,the tablet size is less than about 1000 mg for a dose strength of morethan about 50 mg. In some embodiments, the tablet size is less than 800mg for a dose strength of more than about 100 mg. In some embodiments,the tablet size is less than 600 mg for a dose strength of more thanabout 150 mg. In some embodiment, the tablet size is less than 400 mgfor a dose strength of more than about 200 mg. In some embodiments, thetablet size is less than 400 mg for a dose strength of 100 mg. In someembodiments, the tablet size is less than 200 mg for a dose strength of50 mg. In some embodiments, the tablet size is less than 50 mg for adose strength of 10 mg.

In some embodiments, more than about 20% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 40%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 50% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 60%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 70% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 80%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 20% of the tablet is dissolved in less than24 hours in conventional dissolution media. In some embodiments, morethan about 20% of the tablet is dissolved in less than 12 hours inconventional dissolution media. In some embodiments, more than about 20%of the tablet is dissolved in less than 6 hours in conventionaldissolution media. In some embodiments, more than about 20% of thetablet is dissolved in less than 3 hours in conventional dissolutionmedia. In some embodiments, more than about 20% of the tablet isdissolved in less than 2 hours in conventional dissolution media. Insome embodiments, more than about 20% of the tablet is dissolved in lessthan 60 minutes in conventional dissolution media. In some embodiments,more than about 40% of the tablet is dissolved in less than 60 minutesin conventional dissolution media. In some embodiments, more than about50% of the tablet is dissolved in less than 60 minutes in conventionaldissolution media. In some embodiments, more than about 60% of thetablet is dissolved in less than 60 minutes in conventional dissolutionmedia. In some embodiments, more than about 70% of the tablet isdissolved in less than 60 minutes in conventional dissolution media. Insome embodiments, more than about 80% of the tablet is dissolved in lessthan 60 minutes in conventional dissolution media. In some embodiments,more than about 90% of the tablet is dissolved in less than 60 minutesin conventional dissolution media. In some embodiments, more than about100% of the tablet is dissolved in less than 60 minutes in conventionaldissolution media.

In some embodiments, the tablet is produced at a commercial scale.

In some embodiments, the tablet comprises one or more pharmaceuticallyacceptable excipients.

In some embodiments, the tablet is coated with a coating material, e.g.,a sealant. In some embodiments, the coating material is water soluble.In some embodiments, the coating material comprises a polymer,plasticizer, a pigment, or any combination thereof In some embodiments,the coating material is in the form of a film coating, e.g., a glossyfilm, a pH independent film coating, an aqueous film coating, a drypowder film coating (e.g., complete dry powder film coating), or anycombination thereof. In some embodiments, the coating material is highlyadhesive. In some embodiments, the coating material provides low levelof water permeation. In some embodiments, the coating material providesoxygen barrier protection. In some embodiments, the coating materialallows immediate disintegration for fast release of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the coating material is pigmented, clear, or white. In some embodiments,the coating is an enteric coating. Exemplary coating materials include,without limitation, polyvinylpyrrolidone, polyvinyl alcohol, anacrylate-methacrylic acid copolymer, a methacrylate-methacrylic acidcopolymer, cellulose acetate phthalate, cellulose acetate succinate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, polyvinyl acetate phthalate, shellac, celluloseacetate trimellitate, sodium alginate, zein, and any combinationsthereof.

Pharmaceutically Acceptable Excipients

In some embodiments, the pharmaceutical composition comprises apharmaceutically acceptable excipient. In some embodiments, thecomposition is free of pharmaceutically acceptable excipients. The term“pharmaceutically acceptable excipient”, as used herein, means one ormore compatible solid or encapsulating substances, which are suitablefor administration to a mammal. The term “compatible”, as used herein,means that the components of the composition are capable of beingcommingled with the subject compound, and with each other, in a mannersuch that there is no interaction, which would substantially reduce thepharmaceutical efficacy of the composition under ordinary usesituations. In some embodiments, the pharmaceutically acceptableexcipient is of sufficiently high purity and sufficiently low toxicityto render them suitable for administration preferably to an animal,preferably mammal, being treated.

Some examples of substances, which can serve as pharmaceuticallyacceptable excipients include:

-   -   Amino acids such as alanine, arginine, asparagine, aspartic        acid, cysteine, glutamine, glutamic acid, glycine, histidine,        isoleucine, leucine, lysine, methionine, phenylalanine, proline,        serine, threonine, tryptophan, tyrosine, and valine. In some        embodiments, the amino acid is arginine. In some embodiments,        the amino acid is L-arginine.    -   Monosaccharides such as glucose (dextrose), arabinose, mannitol,        fructose (levulose), and galactose.    -   Cellulose and its derivatives such as sodium carboxymethyl        cellulose, ethyl cellulose, and methyl cellulose.    -   Solid lubricants such as talc, stearic acid, magnesium stearate,        and sodium stearyl fumarate.    -   Polyols such as propylene glycol, glycerin, sorbitol, mannitol,        and polyethylene glycol.    -   Emulsifiers such as the polysorbates.    -   Wetting agents such as sodium lauryl sulfate, Tween®, Span,        alkyl sulphates, and alkyl ethoxylate sulphates.    -   Diluents such as calcium carbonate, microcrystalline cellulose,        calcium phosphate, starch, pregelatinized starch, sodium        carbonate, mannitol, and lactose.    -   Binders such as starches (corn starch and potato starch),        gelatin, sucrose, hydroxypropyl cellulose (HPC),        polyvinylpyrrolidone (PVP), and hydroxypropyl methyl cellulose        (HPMC).    -   Disintegrants such as starch, and alginic acid.    -   Super-disintegrants such as ac-di-sol, croscarmellose sodium,        sodium starch glycolate and crospovidone.    -   Glidants such as silicon dioxide.    -   Coloring agents such as the FD&C dyes.    -   Sweeteners and flavoring agents, such as aspartame, saccharin,        menthol, peppermint, and fruit flavors.    -   Preservatives such as benzalkonium chloride, PHMB,        chlorobutanol, thimerosal, phenylmercuric, acetate,        phenylmercuric nitrate, parabens, and sodium benzoate.    -   Tonicity adjustors such as sodium chloride, potassium chloride,        mannitol, and glycerin.    -   Antioxidants such as sodium bisulfite, acetone sodium bisulfite,        sodium formaldehyde, sulfoxylate, thiourea, and EDTA.    -   pH adjuster such as NaOH, sodium carbonate, sodium acetate, HCl,        and citric acid.    -   Cryoprotectants such as sodium or potassium phosphates, citric        acid, tartaric acid, gelatin, and carbohydrates such as        dextrose, mannitol, and dextran.    -   Cationic surfactants such as cetrimide, benzalkonium chloride        and cetylpyridinium chloride.    -   Anion surfactants such as alkyl sulphates, alkyl ethoxylate        sulphates, soaps, carboxylates, sulfates, and sulfonates.    -   Non-ionic surfactants such as polyoxyethylene derivatives,        polyoxypropylene derivatives, polyol derivatives, polyol esters,        polyoxyethylene esters, poloxamers, glyol esters, glycerol        esters, sorbitan derivatives, polyethylene glycol (PEG-40,        PEG-50, PEG-55), and ethers of fatty alcohols.    -   Organic materials such as carbohydrate and modified        carbohydrates, lactose, a-lactose monohydrate, spray dried        lactose and anhydrous lactose, starch and pre-gelatinized        starch, sucrose, manitol, sorbitol, cellulose, powdered        cellulose and microcrystalline cellulose.    -   Inorganic materials such as calcium phosphates (anhydrous        dibasic calcium phosphate, dibasic calcium phosphate and        tribasic calcium phosphate).    -   Co-processed diluents.    -   Surfactants such as sodium lauryl sulfate.    -   Compression aids.    -   Anti-tacking agents such as silicon dioxide and talc

Amounts

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 500 mg of acompound or pharmaceutically acceptable salt described herein. In someembodiments, the pharmaceutical composition, in the form of a tablet orcapsule, comprises between about 1 mg and about 400 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 300 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 200 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 100 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 90 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 80 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 70 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 60 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 50 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 40 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 30 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 20 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 1 mg and about 10 mg of a compound orpharmaceutically acceptable salt described herein.

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 500 mg of acompound or pharmaceutically acceptable salt described herein. In someembodiments, the pharmaceutical composition, in the form of a tablet orcapsule, comprises between about 10 mg and about 400 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 300 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 200 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 100 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 90 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 80 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 70 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 60 mg of a compound orpharmaceutically acceptable salt described herein f. In someembodiments, the pharmaceutical composition, in the form of a tablet orcapsule, comprises between about 10 mg and about 50 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 40 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 30 mg of a compound orpharmaceutically acceptable salt described herein. In some embodiments,the pharmaceutical composition, in the form of a tablet or capsule,comprises between about 10 mg and about 20 mg of a compound orpharmaceutically acceptable salt described herein.

Particle Size

In some embodiments, the pharmaceutical composition, in the form of atablet or a capsule, comprises a compound or pharmaceutically acceptablesalt described herein, in the form of microparticles. In someembodiments, the microparticles have an average size from about 1 μm toabout 100 μm. In some embodiments, the microparticles have an averagesize from about 1 μm to about 50 μm. In some embodiments, themicroparticles have an average size from about 1 μm to about 30 μm. Insome embodiments, the microparticles have an average size from about 1μm to about 20 μm. In some embodiments, the microparticles have anaverage size from about 5 μm to about 15 μm. In some embodiments, themicroparticles have an average size from about 1 μm to about 10 μm. Insome embodiments, the microparticles have an average size from about 3μm to about 10 μm. In some embodiments, the microparticles have anaverage size from about 4 μm to about 9 μm.

Methods of Treatment

Disclosed herein are methods of treating polycystic ovary syndrome(PCOS) in a subject in need thereof, comprising administering a compoundor pharmaceutically acceptable salt described herein. In someembodiments, the subject in need thereof has PCOS-FAH. In someembodiments, the subject in need thereof has PCOS-FOH+FAH. In someembodiments, the methods described herein result in the reduction of alevel of a hormone. Such hormones include deoxycorticosterone,11-deoxycortisol, cortisol, corticosterone, pregnenolone, 17α-hydroxypregnenolone, progesterone, 17-OHP, dehydroepiandrosterone (DHEA),dehydroepiandrosterone-sulfate (DHEAS), androstenediol, androstenedione(A4), testosterone (T), dihydrotestosterone (DHT), estrone, estradiol,estriol, 11β-hydroxyandrostenedione (110HA4), 11β-hydroxytestosterone(110HT), 11-ketoandrostenedione (11KA4), 11-ketotestosterone (11KT),11β-hydroxy-5α-androstenedione (11OHDHA4), 11-keto-5α-androstenedione(11KDHA4), 11β-hydroxydihydrotestosterone (11OHDHT),11-ketodihydrotestosterone (11KDHT) and ACTH. In some embodiments, themethods described herein result in the reduction of 17-OHP levels. Insome embodiments, the methods described herein result in the reductionof A4 levels. In some embodiments, the methods described herein resultin the reduction of ACTH levels. In some embodiments, the methodsdescribed herein result in the reduction of DHEA levels. In someembodiments, the methods described herein result in the reduction ofDHEAS levels. In some embodiments, the methods described herein resultin the reduction of testosterone (T) levels. In some embodiments, themethods described herein result in the reduction of DHT levels. In someembodiments, the methods described herein result in the reduction of110HA4 levels. In some embodiments, the methods described herein resultin the reduction of 110HT levels. In some embodiments, the methodsdescribed herein result in the reduction of 11KA4 levels. In someembodiments, the methods described herein result in the reduction of11KT levels.

Further, in some embodiments, the methods described herein result in themaintenance of the reduction of 17-OHP, A4, ACTH, DHEA, DHEAS, T, DHT,110HA4, 110HT, 11KA4,and/or 11KT levels. In some embodiments, thereductions of 17-OHP, A4, ACTH, DHEA, DHEAS, T, DHT, 110HA4, 110HT,11KA4 and/or 11KT levels may last for at least 24 hours, 36 hours, 48hours, 60 hours, 72 hours, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 2 years, 5 years, 10years, 15 years, 20 years, 25 years, 30 years, 35 years, 40 years, 45years, 50 years, 55 years, 60 years, 65 years, 70 years, 75 years, 80years, 85 years, 90 years, 95 years, or 100 years.

In some embodiments, the methods described herein result in thereduction of DHEAS levels. In some embodiments, the DHEAS level isreduced by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% from baseline.The baseline level of the DHEAS may be measured in a subject beforebeginning the treatment disclosed herein. In some embodiments, the DHEASlevel is reduced by at least 5% from baseline. In some embodiments, thereduced DHEAS level from baseline may be maintained for at least about 1hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, or 30 weeks.

Further, in some embodiments, the methods described herein result in themaintenance of the reduction of 17-OHP, A4, ACTH, T, DHT, 110HA4, 110HT,11KA4 and/or 11KT levels. In some embodiments, the reductions of 17-OHP,A4, ACTH T, DHT, 11OHA4, 11OHT, 11KA4 and/or 11KT levels may last for atleast 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 4 days, 5 days,6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52weeks, 2 years, 5 years, 10 years, 15 years, 20 years, 25 years, 30years, 35 years, 40 years, 45 years, 50 years, 55 years, 60 years, 65years, 70 years, 75 years, 80 years, 85 years, 90 years, 95 years, or100 years.

In some embodiments, disclosed herein are methods for treating PCOS in asubject in need thereof, and the methods further comprise accessing asource of excessive androgen; and administering a CRF₁ antagonist orpharmaceutically acceptable salt thereof. In some embodiments, accessinga source of excessive androgen comprises measuring the primary source ofexcessive androgen produced in the subject suffering PCOS. In someembodiments, the primary source is the ovaries. In some embodiments, theprimary source is the adrenal glands. In some embodiments, the primarysource is both the ovaries and the adrenal glands. In some embodiments,the primary source is an organ that is able to produce androgen.

In some embodiments, cosyntropin or any other suitable hormones orchemical compounds may be administered to a subject for ACTH response inorder to test for adrenal hyperandrogenism. In some embodiments, thecosyntropin is administered at a dose at least about 0.25, 0.5, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 250orμg/m². In some embodiments, the cosyntropin is administered at a dose atabout the range between the doses disclosed herein. In some embodiments,the cosyntropin is administered at a dose at most about 250, 200, 100,95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10,5, 4, 3, 2, 1 μg/m².

In some embodiments, the subject will be treated for a period of about 1week to about 40 weeks. In some embodiments, the subject will be treatedfor a period of about 2 weeks to about 39 weeks. In some embodiments,the subject will be treated for a period of about 3 weeks to about 38weeks. In some embodiments, the subject will be treated for a period ofabout 4 weeks to about 36 weeks. In some embodiments, the subject willbe treated for a period of about 1 month to 12 months. In someembodiments, the subject will be treated for a period of about 10 monthsto 10 years. In some embodiments, the subject will be treated for aperiod of about 1 months to 10 years. In some embodiments, the subjectwill be treated for a period of about 10 months to 20 years. In someembodiments, the subject will be treated for a period of about 1 monthsto 20 years. In some embodiments, the subject will be treated for aperiod of about 10 months to 30 years. In some embodiments, the subjectwill be treated for a period of about 1 months to 30 years. In someembodiments, the subject will be treated for a period of about 10 monthsto 40 years. In some embodiments, the subject will be treated for aperiod of about 1 months to 40 years. In some embodiments, the subjectwill be treated for a period of about 10 months to 50 years. In someembodiments, the subject will be treated for a period of about 1 monthsto 50 years.

In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt thereof is selected from the group consisting of: Antalarminhydrochloride, CP-154,526, CP-376395 hydrochloride, NBI 27914hydrochloride, NBI 35965 hydrochloride, NGD 98-2 hydrochloride,Pexacerfont, R 121919 hydrochloride, SSR125543 (crinecerfont), ANDSN003.

In some embodiments, the CRF₁ antagonist is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ and R² are independently ethyl or n-propyl;    -   R³ is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy;        and    -   R⁴ is hydrogen, Br, —NR^(a)R^(b), methoxymethyl, n-butyl,        acetamido, pyridin-4-yl, morpholin-4-yl,

and

-   -   R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl,        —CH₂CH₂NH₂, —CH₂CH₂NHC(O)OC(CH₃)₃—CH²CH₂NHC(O)OC(CH₃)₃, or        —CH₂CH₂NHCH₂CH₂CH₃—.

In some embodiments, R³ is F, Cl, Br, methyl, or trifluoromethyl. Insome embodiments, R³ is Cl, Br, or methyl.

In some embodiments, R⁴ is Br, —NR^(a)R_(b)—NR_(a)R_(b), pyridin-4-yl,morpholin-4-yl, or

In some embodiments, R₄ is morpholin-4-yl or

In some embodiments, R₄ is hydrogen, Br, —NR^(a)R^(b) and R^(a) andR^(b) are independently C₁-C₃alkyl.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof

In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt is administered in a dose of about 10 mg to about 200 mg totaldaily dose to the subject. In some embodiments, the CRF₁ antagonist orpharmaceutically acceptable salt is administered in a dose of about 200mg total daily dose to the subject.

In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt is administered in a dose of about 150 mg total daily dose to thesubject. In some embodiments, the CRF₁ antagonist or pharmaceuticallyacceptable salt is administered in a dose of about 100 mg total dailydose to the subject. In some embodiments, the CRF₁ antagonist orpharmaceutically acceptable salt is administered in a dose of about 50mg total daily dose to the subject. In some embodiments, the CRF₁antagonist or pharmaceutically acceptable salt is administered in a doseof about 40 mg total daily dose to the subject. In some embodiments, theCRF₁ antagonist or pharmaceutically acceptable salt is administered in adose of about 30 mg total daily dose to the subject. In someembodiments, the CRF₁ antagonist or pharmaceutically acceptable salt isadministered in a dose of about 25 mg total daily dose to the subject.In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt is administered in a dose of about 20 mg total daily dose to thesubject. In some embodiments, the CRF₁ antagonist or pharmaceuticallyacceptable salt is administered in a dose of about 15 mg total dailydose to the subject. In some embodiments, the CRF₁ antagonist orpharmaceutically acceptable salt is administered in a dose of about 10mg total daily dose to the subject. In some embodiments, the CRF₁antagonist or pharmaceutically acceptable salt is administered in a doseof about 5 mg total daily dose to the subject.

In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt is in the form of microparticles. In some embodiments, the averagesize of the microparticles is between about 1 μm to about 20 μm. In someembodiments, the average size of the microparticles is between about 5μm to about 15 μm. In some embodiments, the average size of themicroparticles is less than about 10 μ.

In some embodiments, the CRF₁ antagonist or pharmaceutically acceptablesalt thereof is administered as a pharmaceutical composition. In someembodiments, the steroid or a pharmaceutically acceptable salt thereofis administered as a pharmaceutical composition.

In some embodiments, the pharmaceutical composition is in the form of acapsule or a tablet. In some embodiments, the capsule is a hard gelatincapsule. In some embodiments, the capsule is a soft gelatin capsule. Insome embodiments, the capsule is formed using materials selected fromthe group consisting of natural gelatin, synthetic gelatin, pectin,casein, collagen, protein, modified starch, polyvinylpyrrolidone,acrylic polymers, cellulose derivatives, and any combinations thereof.

In some embodiments, the pharmaceutical composition is free ofadditional excipients. In some embodiments, the pharmaceuticalcomposition further comprises one or more pharmaceutically acceptableexcipients. In some embodiments, the pharmaceutical composition is inthe form of a tablet. In some embodiments, the pharmaceuticalcomposition further comprises one or more pharmaceutically acceptableexcipients.

In some embodiments, CRF₁ antagonist or pharmaceutically acceptable saltis formulated as a capsule or a tablet as to provide a Tmax of about 1to about 8 hours in a subject. In some embodiments, CRF₁ antagonist orpharmaceutically acceptable salt is formulated as a capsule or a tabletas to provide a Tmax of about 2 to about 7 hours in a subject. In someembodiments, CRF₁ antagonist or pharmaceutically acceptable salt isformulated as a capsule or a tablet as to provide a Tmax of about 2 toabout 6 hours in a subject. In some embodiments, CRF₁ antagonist orpharmaceutically acceptable salt is formulated as a capsule or a tabletas to provide a Tmax of about 3 to about 5 hours in a subject.

In some embodiments, CRF₁ antagonist or pharmaceutically acceptable saltis formulated as a capsule or a tablet as to provide a Tmax of about 8hours in a subject. In some embodiments, CRF₁ antagonist orpharmaceutically acceptable salt is formulated as a capsule or a tabletas to provide a Tmax of about 7 hours in a subject. In some embodiments,CRF₁ antagonist or pharmaceutically acceptable salt is formulated as acapsule or a tablet as to provide a Tmax of about 6 hours in a subject.In some embodiments, CRF₁ antagonist or pharmaceutically acceptable saltis formulated as a capsule or a tablet as to provide a Tmax of about 5hours in a subject. In some embodiments, CRF₁ antagonist orpharmaceutically acceptable salt is formulated as a capsule or a tabletas to provide a Tmax of about 4 hours in a subject. In some embodiments,CRF₁ antagonist or pharmaceutically acceptable salt is formulated as acapsule or a tablet as to provide a Tmax of about 3 hours in a subject.In some embodiments, CRF₁ antagonist or pharmaceutically acceptable saltis formulated as a capsule or a tablet as to provide a Tmax of about 2hours in a subject. In some embodiments, CRF₁ antagonist orpharmaceutically acceptable salt is formulated as a capsule or a tabletas to provide a Tmax of about 1 hour in a subject.

In some embodiments, the methods described herein include administrationof the pharmaceutical composition comprising CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof once a month, twice a month, three times a month,once a week, twice a week, three times a week, once every two days, oncea day, twice a day, three times a day, or four times a day. In someembodiments, the methods described herein administer CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof once a day. In some embodiments, the methodsdescribed herein administer CRF₁ antagonist or pharmaceuticallyacceptable salt, or a pharmaceutically acceptable salt or solvatethereof twice a day.

In some embodiments, the methods described herein include administrationof about 1 mg to about 2000 mg of CRF₁ antagonist or pharmaceuticallyacceptable salt, or a pharmaceutically acceptable salt or solvatethereof, per day. In some embodiments, CRF₁ antagonist orpharmaceutically acceptable salt is administered at a dose between about50 mg/day and about 1600 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 50 mg/day and about 1500 mg/day. Insome embodiments, Compound 3 is administered at a dose between about 50mg/day and about 1400 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 50 mg/day and about 1300 mg/day. Insome embodiments, Compound 3 is administered at a dose between about 50mg/day and about 1200 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 50 mg/day and about 1100 mg/day. Insome embodiments, Compound 3 is administered at a dose between about 50mg/day and about 1000 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 50 mg/day and about 900 mg/day. Insome embodiments, Compound 3 is administered at a dose between about 50mg/day and about 800 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 60 mg/day and about 800 mg/day. Insome embodiments, Compound 3 is administered at a dose between about 70mg/day and about 800 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 80 mg/day and about 800 mg/day. Insome embodiments, Compound 3 is administered at a dose between about 90mg/day and about 800 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 100 mg/day and about 800 mg/day. Insome embodiments, Compound 3 is administered at a dose between about 100mg/day and about 700 mg/day. In some embodiments, Compound 3 isadministered at a dose between about 100 mg/day and about 600 mg/day. Insome embodiments, Compound 3 is administered at a dose between 150mg/day and about 600 mg/day. In some embodiments, Compound 3 isadministered at a dose between 200 mg/day and about 600 mg/day. In someembodiments, Compound 3 is administered at a dose between 200 mg/day andabout 500 mg/day. In some embodiments, Compound 3 is administered at adose between 200 mg/day and about 400 mg/day. In some embodiments,Compound 3 is administered at a dose between 25 mg/day and about 200mg/day.

In some embodiments, Compound 3 is administered at a dose of about 500mg/day. In some embodiments, Compound 3 is administered at a dose ofabout 400 mg/day. In some embodiments, Compound 3 is administered at adose of about 300 mg/day. In some embodiments, Compound 3 isadministered at a dose of about 200 mg/day. In some embodiments,Compound 3 is administered at a dose of about 150 mg/day. In someembodiments, Compound 3 is administered at a dose of about 100 mg/day.In some embodiments, Compound 3 is administered at a dose of about 50mg/day.

In some embodiments, about 50 mg to about 1600 mg of CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, about100 mg to about 1600 mg of CRF₁ antagonist or pharmaceuticallyacceptable salt, or a pharmaceutically acceptable salt or solvatethereof, is administered per day. In some embodiments, about 200 mg toabout 1600 mg of CRF₁ antagonist or pharmaceutically acceptable salt, ora pharmaceutically acceptable salt or solvate thereof, is administeredper day. In some embodiments, about 200 mg to about 1200 mg of CRF₁antagonist or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable salt or solvate thereof, is administered per day. In someembodiments, about 200 mg to about 1000 mg of CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, about200 mg to about 800 mg of CRF₁ antagonist or pharmaceutically acceptablesalt, or a pharmaceutically acceptable salt or solvate thereof, isadministered per day. In some embodiments, about 100 mg to about 800 mgof CRF₁ antagonist or pharmaceutically acceptable salt, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, about 200 mg to about 800 mg of CRF₁antagonist or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable salt or solvate thereof, is administered per day. In someembodiments, about 100 mg to about 600 mg of CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, about200 mg to about 600 mg of CRF₁ antagonist or pharmaceutically acceptablesalt is administered per day. In some embodiments, about 300 mg to about600 mg of CRF₁ antagonist or pharmaceutically acceptable salt, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, about 100 mg to about 400 mg of CRF₁antagonist or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable salt or solvate thereof, is administered per day. In someembodiments, about 200 mg to about 400 mg of CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, about300 mg to about 400 mg of CRF₁ antagonist or pharmaceutically acceptablesalt, or a pharmaceutically acceptable salt or solvate thereof, isadministered each day.

In some embodiments, less than about 2000 mg CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, lessthan about 1800 mg CRF₁ antagonist or pharmaceutically acceptable salt,or a pharmaceutically acceptable salt or solvate thereof, isadministered per day. In some embodiments, less than about 1600 mg CRF₁antagonist or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable salt or solvate thereof, is administered per day. In someembodiments, less than about 1400 mg CRF₁ antagonist or pharmaceuticallyacceptable salt, or a pharmaceutically acceptable salt or solvatethereof, is administered per day. In some embodiments, less than about1200 mg CRF₁ antagonist or pharmaceutically acceptable salt, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 1000 mg CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, lessthan about 800 mg CRF₁ antagonist or pharmaceutically acceptable salt,or a pharmaceutically acceptable salt or solvate thereof, isadministered per day. In some embodiments, less than about 600 mg CRF₁antagonist or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable salt or solvate thereof, is administered per day. In someembodiments, less than about 500 mg CRF₁ antagonist or pharmaceuticallyacceptable salt, or a pharmaceutically acceptable salt or solvatethereof, is administered per day. In some embodiments, less than about400 mg CRF₁ antagonist or pharmaceutically acceptable salt, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 300 mg CRF₁ antagonist orpharmaceutically acceptable salt, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, lessthan about 200 mg CRF₁ antagonist or pharmaceutically acceptable salt,or a pharmaceutically acceptable salt or solvate thereof, isadministered per day.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein wherein the subjectis in the fed state. In some embodiments, the methods described hereininclude administration of the pharmaceutical compositions describedherein wherein the subject is in the fasted state.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein at bedtime.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein less than about 4hours before sleep. In some embodiments, the methods described hereininclude administration of the pharmaceutical compositions describedherein less than about 3 hours before sleep. In some embodiments, themethods described herein include administration of the pharmaceuticalcompositions described herein less than about 2 hours before sleep. Insome embodiments, the methods described herein include administration ofthe pharmaceutical compositions described herein less than about 1 hourbefore sleep. In some embodiments, the methods described herein includeadministration of the pharmaceutical compositions described herein lessthan about 30 mins before sleep.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein in the evening.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein at about 11 pm atnight. In some embodiments, the methods described herein includeadministration of the pharmaceutical compositions described herein atabout 10 pm at night. In some embodiments, the methods described hereininclude administration of the pharmaceutical compositions describedherein at about 9 pm at night. In some embodiments, the methodsdescribed herein include administration of the pharmaceuticalcompositions described herein at about 8 pm at night.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein in combination witheflornithine and/or retinoids. In some embodiments, the methodsdescribed herein include administration of the pharmaceuticalcompositions described herein in combination with contraceptive pillscontaining androgen receptor blockers such as cyproterone acetate,spironolactone, flutamide, or 5α-reductase inhibitors.

In some embodiments, the levels of DHEA, DHEAS, A4, 11OHA4, T, 110HT,DHT and/or ACTH in the subject are determined from a biological samplefrom the subject. In some embodiments, the biological sample is selectedfrom the group of blood, blood fractions, plasma, serum, urine, othertypes of bodily secretions, and saliva. In some embodiments, thebiological sample is obtained non-invasively.

In some embodiments, the subject is a pediatric patient. In someembodiments, the subject is an adolescent. In some embodiments, thesubject is from about 8 years old to about 18 years old. In someembodiments, the subject is an adult patient. In some embodiments, thesubject is from about 18 years old to about 55 years old. In someembodiments, the subject is from about 18 years old to about 50 yearsold.

In some embodiments, the steroid and the CRF₁ antagonist areadministered concurrently. In some embodiments, the steroid and the CRF₁antagonist are administered in one pharmaceutical composition. In someembodiments, the steroid and the CRF₁ antagonist are administeredconcurrently in separate pharmaceutical compositions. In someembodiments, the steroid and the CRF₁ antagonist are administeredsequentially.

EXAMPLES

The following examples further illustrate the invention but should notbe construed as in any way limiting its scope. In particular, theprocessing conditions are merely exemplary and can be readily varied byone of ordinary skill in the art.

All methods described herein can be performed in a suitable order unlessotherwise indicated herein or otherwise clearly contradicted by context.The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. Unless defined otherwise, technical and scientificterms used herein have the same meaning as is commonly understood by oneof skill in the art to which this invention belongs.

Example 1—Reduction of DHEAS level in a subject who has polycystic ovarysyndrome (PCOS) and elevated adrenal androgens

Study Compound 3 in a double-blind, proof-of-concept study, evaluatingthe safety and efficacy of repeated doses of Compound 3 in adults withelevated adrenal androgens, PCOS-FAH or PCOS-FAH+FOH. After screening,eligible subjects with elevated adrenal androgens documented by elevatedDHEAS will be randomized to either a compound 3 dose escalation arm ormatching placebo arm.

The study is planned as a 3-period study with a duration of 4 weeks forPeriods 1 and 2 and a duration of 8 weeks in Period 3 for a totaltreatment duration of 16 weeks. Subjects randomized to the compound 3dose escalation arm will be treated with escalating doses of 50-mg,100-mg or 200 mg based on achieving a DHEAS positive response criteriawithin each treatment period. Subjects not meeting the criteria will bedose escalated to the next highest dose in the preceding period.Subjects meeting the criteria will remain on their current dose level.Placebo subjects will remain on placebo through the full 16 weeks.

The population are composed of approximately 40 patients, who receiveCompound 3 or matching placebo daily for up to 16 weeks. Compound 3 isadministered as an oral daily dose. Patients are undergo PK/PD or PDonly assessments, approximately every 2 weeks. A follow-up outpatientvisit occurs 30 days after the last dose.

Study Design

-   -   Study Type: Interventional    -   Primary Purpose: Treatment    -   Study Phase: Phase 2    -   Interventional Study Model: Randomized    -   Number of Arms: 2    -   Masking: Masking of Study drug    -   Allocation: Randomized (1:1)    -   Enrollment: 40

Arms and Interventions:

Arms Assigned Intervention Arm 1 Drug: Compound 3 dose escalation (50,100 and 200-mg) Arm 2 Drug: Matching Placebo

Outcome Measures Primary Outcome Measures:

-   -   1. Safety and tolerability of Compound 3 in patients with        elevated adrenal androgens (adverse effects, serious adverse        effects, clinical laboratory parameters, etc.)        [Time Frame: 16 weeks]

Secondary Outcome Measures:

-   -   2. Proportion of subjects with:        -   a. ≥30% change from baseline in dehydroepiandrosterone            sulfate (DHEAS)        -   b. DHEAS<upper limit of normal (ULN)        -   c. DHEAS<75^(th) percentile of normal range (Q3)            [Time Fame: 4 to up to 16 weeks]    -   3. Pharmacokinetics of compound 3        [Time Frame: 4 weeks]

Exploratory Outcome Measure:

-   -   4. Changes in PD markers: Changes in cortisol, ACTH, DHEAS,        DHEA, A4, T, 17-OHP, 110HA4, 110HT, 11KA4, 11KT        [Time Frame: up to 16 weeks]

Eligibility

-   -   Minimum Age: 18 Years    -   Maximum Age: 30 years    -   Sex: Female only    -   Gender Based: Yes    -   Accepts Healthy Volunteers: No    -   Criteria: Inclusion

Criteria: Inclusion Criteria:

-   -   Female subjects 18 to 30 years old, inclusive    -   Subjects must have documented PCOS according to the NIH (1990)        criteria    -   BMI ≤38 kg/m²    -   DHEAS level>age matched reference ULN at Screening    -   Evidence of DHEA hyperresponsiveness to ACTH stimulation during        Screening

Exclusion Criteria:

-   -   Has a BMI >38kg/m²    -   Has PCOS-FOH    -   Has HbA1c>6.5% or Fasting plasma glucose >126 mg/dL    -   Has a history that includes bilateral adrenalectomy or        hypopituitarism    -   Has a history of allergy or hypersensitivity to tildacerfont or        any other CRF₁ receptor antagonist    -   Clinically significant unstable medical condition, illness, or        chronic disease    -   Clinically significant uncontrolled psychiatric disorder    -   Clinically significant abnormal laboratory finding or assessment    -   Pregnant or nursing females    -   Use of any other investigational drug within 30 days    -   Unable to understand and comply with the study procedures,        understand the risks, and/or unwilling to provide written        informed consent.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. It is not intendedthat the invention be limited by the specific examples provided withinthe specification. While the invention has been described with referenceto the aforementioned specification, the descriptions and illustrationsof the embodiments herein are not meant to be construed in a limitingsense. Numerous variations, changes, and substitutions will now occur tothose skilled in the art without departing from the invention.Furthermore, it shall be understood that all aspects of the inventionare not limited to the specific depictions, configurations or relativeproportions set forth herein which depend upon a variety of conditionsand variables. It should be understood that various alternatives to theembodiments of the invention described herein may be employed inpracticing the invention. It is therefore contemplated that theinvention shall also cover any such alternatives, modifications,variations or equivalents. It is intended that the following claimsdefine the scope of the invention and that methods and structures withinthe scope of these claims and their equivalents be covered thereby.

1. (canceled)
 2. A method of treating polycystic ovary syndrome withfunctional adrenal hyperandrogenism (PCOS-FAH) in a subject in needthereof, comprising administering a CRF₁ antagonist or pharmaceuticallyacceptable salt thereof.
 3. The method of claim 2, wherein said CRF₁antagonist is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently ethyl or n-propyl; R³ is hydrogen, F, Cl, Br, methyl,trifluoromethyl, or methoxy; R⁴ is hydrogen, Br, —NR^(a)R^(b),methoxymethyl, n-butyl, acetamido, pyridin-4-yl, morpholin-4-yl,

R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl, —CH₂CH₂NH₂,—CH₂CH₂NHC(O)OC(CH₃)₃, or —CH₂CH₂NHCH₂CH₂CH₃.
 4. (canceled)
 14. Themethod of claim 3, wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof
 15. The method of claim 2,wherein said CRF₁ antagonist or pharmaceutically acceptable salt thereofis selected from the group consisting of: Antalarmin hydrochloride,CP-154,526, CP-376395 hydrochloride, NBI 27914 hydrochloride, NBI 35965hydrochloride, NGD 98-2 hydrochloride, Pexacerfont, R 121919hydrochloride, SSR125543 (crinecerfont), and SN003.
 16. The method ofclaim 2, wherein the CRF₁ antagonist or pharmaceutically acceptable saltis administered in a dose of about 5 mg to about 400 mg total daily doseto the subject.
 17. The method of claim 2, wherein the CRF₁ antagonistor pharmaceutically acceptable salt is administered in a dose of about300 mg total daily dose to the subject.
 18. The method of claim 2,wherein the CRF₁ antagonist or pharmaceutically acceptable salt isadministered in a dose of about 200 mg total daily dose to the subject.19. The method of claim 2, wherein the CRF₁ antagonist orpharmaceutically acceptable salt is administered in a dose of about 150mg total daily dose to the subject.
 20. The method of claim 2, whereinthe CRF₁ antagonist or pharmaceutically acceptable salt is administeredin a dose of about 100 mg total daily dose to the subject.
 21. Themethod of claim 2, wherein the CRF₁ antagonist or pharmaceuticallyacceptable salt is administered in a dose of about 75 mg total dailydose to the subject.
 22. The method of claim 2, wherein the CRF₁antagonist or pharmaceutically acceptable salt is administered in a doseof about 50 mg total daily dose to the subject.
 23. The method of claim2, wherein the CRF₁ antagonist or pharmaceutically acceptable salt isadministered in a dose of about 25 mg total daily dose to the subject.24. The method of claim 2, wherein the CRF₁ antagonist orpharmaceutically acceptable salt is administered in a dose of about 10mg total daily dose to the subject.
 25. (canceled)
 26. (canceled) 27.The method of one claim 2, wherein an adrenocorticotropic hormone (ACTH)level is reduced by at least 10% from baseline.
 28. (canceled)
 29. Themethod of any claim 2, wherein a dehydroepiandrosterone sulfate (DHEAS)level is reduced by at least 10% from baseline.
 30. (canceled)
 31. Themethod of claim 2, wherein androstenedione (A4) level is reduced by atleast 10% from baseline.
 32. (canceled)
 33. The method of claim 2,wherein 1β-hydroxyandrostenedione (110HA4) level is reduced by at least10% from baseline.
 34. (canceled)
 35. The method of claim 2, wherein11β-hydroxytestosterone (11OHT) level is reduced by at least 10% frombaseline.
 36. The method of claim 31, wherein said reduced A4 level frombaseline is maintained for at least 24 hours. 37.-39. (canceled)
 40. Themethod of claim 14, wherein the compound of Formula (I) is administeredat a dose between about 1 mg/day and about 200 mg/day. 41.-47 (canceled)48. The method of claim 2, wherein the pharmaceutical composition is inthe form of microparticles. 49.-51 (canceled)
 52. The method of claim 2,wherein the pharmaceutical composition is in the form of a capsule or atablet. 53.-59 (canceled)
 60. The method of claim 2, wherein the subjectis a pediatric patient or an adult patient. 61.-66 (canceled)